West Nile virus (WNV) is the most significant cause of viral encephalitis in the USA, responsible for over 1400 lethal human meningoencephalitis cases since 1999. Addressing the fundamental questions regarding host-WNV interactions is an integrated and indispensable part of the effort towards development of vaccines and therapeutics. This project will investigate the critical role of NLRP6, a poorly characterized member of the NOD (nucleotide- binding oligomerization domain) like receptor (NLR) family, in controlling WNV pathogenesis in mice. NLRP6 has been recently demonstrated to play a protective role in development of chemically induced colitis as well as colitis-induced tumorigenesis, and to maintain the gut microbiome homeostasis by preventing inflammation-inducing bacteria from colonizing the colon. More recently, NLRP6 was shown to negatively regulate NF-kB signaling during bacterial infection. However, our results show that NLRP6 helps mammalian hosts fight against WNV infection and reduce WNV lethality by enhancing type I IFN response. This project will continue investigating the physiological functions of NLRP6 in WNV infection in vivo, and elucidate the underlying mechanisms through biochemical, molecular and genetic approaches.